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Dosage Adjustment for Cytotoxics in Renal
Impairment
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January 2009
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Dosage Adjustment for Cytotoxics in Renal Impairment
This table is a guide only. Pharmacokinetic, Summary of Product Characteristics (SPC), relevant pharmaceutical company data and various references have been
reviewed for each drug. From this information, a recommendation has been suggested. Input of the full clinical picture of the patient should always be taken into
account. As limited data is available, the scope of the document applies to adult data. If paediatric data is obtainable, this has been included. If a patient is following a
specific clinical trial or protocol, it is advisable to follow the associated dose modifications.
The BNF (Edition 59) states (from Chronic kidney disease in adults: UK guidelines for identification, management and referral (March 2006):
Degree of Impairment
Normal
Mild
Moderate
Severe
Established renal failure
Drug
eGFR mL/min/1.73m2 (GFR = eGFR x BSA/1.73)
More than 90 (with other evidence of kidney damage)
60 – 89 (with other evidence of kidney damage)
30 – 59
15 – 29
Less than 15
Pharmacokinetics
Available Information
Recommendation
Alemtuzumab
t1/2 23 – 30 hours.
Serum concentration rise
corresponds with reduction in
malignant lymphocytosis. Different
pharmacokinetic properties may be
related to different tumour burden
and distribution.
Alemtuzumab is primarily
metabolised intracellularly.
SPC (Bayer 2008) – No studies have been conducted in patients with renal
impairment.
Schering – Unlikely to require a reduction. Cleared intracellularly. Treatment
is not recommended.
BC Cancer Agency – No information found.
Clinical Decision
Amsacrine
Amsacrine is extensively
metabolised in the liver. The
principal metabolites, via
microsomal oxidation, are much
more cytotoxic than the parent
drug. Excretion is via the bile.
>50% excreted in faeces within 2
hours; 35% in urine.
SPC (Goldshield 2007) – for patients with impaired renal function, reduce dose
by 20-30% (to 60-75mg/m2 per day).
BC Cancer Agency – Reduce dose by 25% if serum creatinine is >140µmol/L
AML 17 - If renal function is reduced (Cr Cl < 60ml/min) the dose should be
reduced by 25%.
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux, CAV/VVHD - Dose as
in renal impairment – 60-75mg/m2 daily.
If CrCl < 60ml/min, reduce dose by
25%
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
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Drug
Pharmacokinetics
Available Information
Recommendation
Arsenic Trioxide
Arsenic is stored mainly in liver,
kidney, heart, lung, hair and nails.
Trivalent forms of arsenic are
methylated in humans and mostly
excreted in urine.
SPC (Cephalon 2008) – Safety and effectiveness of arsenic trioxide in patients
with renal impairment have not been studied. Caution is needed in patients with
renal impairment as this is the main route of elimination.
Cephalon – A phase I, multicentre, open label, non-randomised study of arsenic
trioxide injection was performed to establish the safety of the drug in patients
with renal impairment. Twenty patients with varying renal function were
included. Patients that had severe renal dysfunction (GFR<30mls/min) had a
mean AUC value 48% greater than patients with normal renal function.
Systemic exposure to metabolites of arsenic trioxide was also greater in the
renally impaired groups of patients. No increased toxicity was noted but the
clinical consequences were unknown. Toxicity profile across all groups of renal
impairment was similar.
Clinical decision – consider dose
reduction in GFR<30mls/min.
ATRA (tretinoin)
After an oral dose of radiolabelled
tretinoin, about 60% of the
radioactivity was excreted in urine
and about 30% in faeces. The
metabolites found in urine were
formed by oxidation and
glucuronidation.
SPC (Roche 2008) – due to limited information on patients with renal
insufficiency, reduce dose to 25mg/m2 as a precautionary measure.
BC cancer agency – as above.
Reduce dose to 25mg/m2 in renal
impairment.
Azacitadine
Azacitadine undergoes rapid
elimination. The route of
elimination requires further study.
The drug appears to undergo
metabolism. Excretion of
unchanged drug and metabolites is
via the kidneys. The activity of
metabolites is unknown.
Pharmion – Recommended starting dose is 75mg/m2 SC daily for 7 days. No
dose adjustment of initial dose based on renal function is recommended. If
unexplained reductions in serum bicarbonate or elevations in serum creatinine,
or BUN occur, the dosage should be reduced by 50% on the next course. The
start of the next cycle should be delayed until values return to normal.
No dose reductions necessary for 1st
cycle.
Bevacizumab
Terminal half-life 19-20 days
SPC (Roche 2008) – Safety and efficacy has not been studied in this group of
patients
Roche – preclinical studies in animal models indicated no adverse effects in
renal dysfunction.
Dialysis
Inauen et al reported a case where bevacizumab was well tolerated with
haemodialysis without a dose reduction1.
Renal Drug Handbook – bevacizumab has been used in a haemodialysis
patient at a dose of 5mg/kg every 14 days.
Clinical decision
Bexarotene
Metabolised by oxidation via
CYP450 3A4 and glucuronidation.
Less than 1% excreted in the urine.
SPC (Cephalon 2007) – No formal studies have been performed in this group
of patients. Renal excretion is not a significant elimination pathway.
Clinical decision – unlikely to require
reduction unless severe renal
impairment.
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Drug
Bleomycin
Bortezomib
Pharmacokinetics
Available Information
t½ 2-4 hours.
Rapid distribution to body tissues
(highest concn in skin, lungs,
peritoneum & lymph). Inactivation
takes place primarily in the liver. ~
2/3 of drug is excreted unchanged
in the urine, probably by glomerular
filtration.
SPC (Mayne pharma) – If creatinine 177-354mol/L, give 50% dose. If
creatinine >354mol/L, further reduction is necessary. The rate of excretion is
highly influenced by renal function; concentrations in plasma are greatly
elevated if usual doses are given to patients with renal impairment with only up
to 20% excreted in 24 hours. Observations indicate that it is difficult to
eliminate bleomycin by dialysis.
Kyowa Hakko – As above and bleomycin should be used with caution in
patients with significant renal impairment as clearance may be reduced and
toxicity increased. NB when GFR ~<30ml/min patient may be at increased risk
of developing lung dysfunction.
Faulding – suggested dose modification schedule: CrCl 10-50ml/min – 75%
dose. CrCl < 10ml/min, give 50% dose.
Renal Drug Handbook – GFR 20-50mls/min - dose as in normal renal
function, 10-20mls/min give 75% of dose, <10mls/min – 50% of normal dose.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High Flux – 50% dose.
CAV/VVHD – 75% dose.
CrCl (ml/min)
Dose
>50
10-50
<10
100%
75%
50%
Metabolised by oxidative
debronation via CYP450 3A4,
2C19 and 1A2. Small amount
excreted in the urine. Terminal t½
is 9-15 hours.
SPC (Janssen Cilag 2008) – The pharmacokinetics of bortezomib are not
influenced in patients with renal impairment (CrCl> 20 ml/min/1.73 m2);
therefore, dosing adjustments are not necessary for these patients. It is unknown
if the pharmacokinetics are influenced in patients with severe renal impairment
(CrCl < 20 ml/min/1.73m2 not undergoing dialysis). Since dialysis may reduce
bortezomib concentrations, the drug should be administered after the dialysis
procedure.
BC Cancer Agency – Use with caution in renal impairment.
Renal Drug Handbook – GFR 30-50ml/min dose as in normal renal function,
GFR 10-30ml/min dose as in normal renal function. Monitor carefully. GFR<10
a reduced dose may be required. Normal doses have been used in GFR 1030ml/min with increased risk of adverse effects. Some trials have used doses of
1mg/m2 in patients with GFR 10-30ml/min with similar efficacy and incidence
of side effects.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux –Consider dose
reduction. CAV/VVHD – Dose as in normal renal function.
Clinical decision – consider reduction
if GFR<20mls/min
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
Page 4 of 24
Drug
Pharmacokinetics
Available Information
Busulfan
The mean elimination t½ is 2.57hrs.
Extensive hepatic metabolism to at
least 12 methanesulfonic acid, and
metabolites. After low and high
doses, 1 & 2% respectively of
unchanged drug is excreted in the
urine. The majority of an oral dose
is excreted in the urine as inactive
metabolite.
SPC (Pierre Fabre 2008) – Studies have not been conducted in renally
impaired patients. Caution is recommended in this group.
Glaxo Wellcome – although very little unmetabolised drug is excreted in the
urine, a complex range of metabolites are excreted by this route. The
administration of high-dose busulphan has been evaluated in 15 patients with
multiple myeloma (4 had CrCl < 30ml/min) with no problems2.
BC Cancer Agency – no information found
Dialysis
Ullery et al, 2000- A published case report demonstrated that haemodialysis
effectively cleared busulfan. Exposure to busulfan was not significantly
altered3.
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD – Dose as
in normal renal function.
No dose reduction necessary.
Capecitabine
Extensive absorption (~70%) after
food intake. Metabolism is first in
the liver and then in the tumour. Up
to 96% dose is recovered in the
urine. Terminal t½ = 0.75 hours.
SPC (Roche 2009) – capecitabine is contra-indicated in patients with severe
renal impairment (CrCl <30 ml/min) The incidence of grade 3-4 toxicities in
patients with moderate renal impairment (CrCl 30-50 ml/min) is increased. An
initial dose of 75% of the 1250mg/m2 starting dose is recommended. In patients
with mild renal impairment (CrCl 51-80ml/min), no adjustment of the starting
dose is recommended. Careful monitoring and prompt treatment interruption is
recommended if the patient develops a grade 2, 3, or 4 adverse event, followed
by the appropriate dose adjustment.
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux. CAV/VVHD – Avoid
CrCl (ml/min)
Dose
51-80
30-50
<30
100%
75%
CI
There is little, if any, true
metabolism of carboplatin.
Excretion is primarily by
glomerular filtration in urine, with
most of the drug excreted in the
first 6hrs. ~32% dose is excreted
unchanged.
Terminal t½ ~ 6 days.
SPC (Hospira 2006) – Dose reduce with renal impairment and monitor
haematological nadirs and renal function. Myelosuppression is closely related
to renal clearance. Carboplatin is contra-indicated with CrCl <20ml/min.
Faulding – CrCl >40ml/min, max dose = 400mg/m2
CrCl 20-39ml/min, max dose = 250mg/m2
Dialysis
BC Cancer Agency – In dialysis dependant chronic renal failure give a fixed
dose of 100mg, if the patient has had previous platinum treatment, or 150mg if
not. Dialysis should be performed 24 hours after the dose.
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Dose as
in normal renal function.
Dose using Calvert equation:
Dose = AUC(25 + GFR)
Carboplatin
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
CI if CrCl <20ml/min
Page 5 of 24
Drug
Pharmacokinetics
Available Information
Partially metabolised to active
species by liver microsomal
enzymes, which have a long t½. It
is thought that the antineoplastic
activity may be due to metabolites.
~60-70% of the total dose is
excreted in the urine in 96hrs and
~10% as respiratory CO2.
Terminal t½ ~ 1 hour.
SPC (Bristol Myers 2007) – no information.
BMS – very little information. Clinical decision based on the haematological
response to previous doses and monitoring blood counts.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl
of 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, carmustine is not
recommended
BC Cancer Agency - GFR <10ml/min discontinue
The Renal Handbook – dose as in normal function.
Dialysis
BMS – Carmustine is not dialysed. Dose adjustment is not required in patients
undergoing renal replacement therapy. Includes CAPD, HD, and continuous
arterio-venous/veno-venous haemodiafiltration5.
Boesler et al, 2005- documented cases where carmustine was used with a dose
reduction in patients having haemodialysis. Doses escalated and reduced
depending on white cell count6.
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Dose as
in normal renal function.
CrCl (ml/min)
Dose
60
45
<30
80%
75%
Clinical decision
Cetuximab
Elimination is via binding EGFRs
in a large number of tissues. Half
life =3-7 days.
SPC (Merck Sorono 2008) – Only patients with adequate renal function have
been investigated.
Merck – No recommended dose adjustment, not studied in this group of
patients, not contraindicated.
Dialysis
Inauen et al reported a case where cetuximab was well tolerated with
haemodialysis without a dose reduction 1.
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Not
dialysed, dose as in normal renal function.
Clinical decision – unlikely to require
a reduction.
Chlorambucil
Good oral absorption - absorption
slowed and decreased by 10-20% if
ingested with food. Metabolism
predominantly in liver via hepatic
microsomal enzyme oxidation
system. <1% excreted unchanged
in the urine. t½ = 2 hours.
SPC (GSK 2007) – monitor patients with evidence of impaired renal function
as prone to additional myelosuppression associated with azotaemia.
Glaxo Wellcome – very little information. Renal function does not appear to
affect the elimination rate. Chlorambucil is unlikely to be dialysed.
Renal Drug Handbook – no dose reduction necessary.
BC Cancer Agency – increased risk of myelosuppression
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Dose as
in normal renal function.
No dose reductions necessary,
however, monitor patients carefully,
as they are more prone to
myelosuppression.
Carmustine
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
Dialysis – reference source suggests
that no dose reduction required. This
is confirmed by various renal
handbooks, however, dose reductions
are recommended for patients with
renal impairment in these handbooks.
Therefore, clinical decision.
Dialysis – not dialysed, dose as in
normal renal function.
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Drug
Pharmacokinetics
Available Information
Recommendation
Chlormethine
(Mustine)
Following intravenous injection, it
is rapidly converted to a reactive
ethyleneimmonium ion. Usually
disappears from the blood within
approximately ten minutes. t1/2 15
minutes. Less than 0.01% of drug is
excreted unchanged in the urine.
50% excreted in the urine as
metabolites after 24 hours.
SPC - no information available
No information available.
Probably no dose reduction
necessary.
Clinical decision
Cisplatin
Non-enzymatically transformed
into multiple metabolites. There is
good uptake of cisplatin in the
kidneys, liver and intestine.
Distributes into third spaces such as
ascites and pleural fluid. The
elimination of intact drug and
metabolites is via the urine. In the
first 24hrs 20-80% is excreted.
SPC (Pharmacia 2008) – Cisplatin induces nephrotoxicity, which is
cumulative. It is therefore contra-indicated in patients with renal impairment.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.75 fraction of dose, for CrCl
of 45ml/min, use 0.5 fraction of dose, for CrCl of 30ml/min cisplatin is contraindicated.
BC Cancer Agency –GFR>60mls/min ; 100%, GFR 45-59mls/min; 75% dose,
<45mls/min ; hold cisplatin- delay with hydration/switch to carboplatin.
Bennett et al7 – GFR >50mls/min 100% dose; GFR 10-50mls/min 75% dose
GFR <10mls/min 50% dose
Dialysis
Haemodialysis – Dialysed. Give 50% dose7
NB. There is experience of using the same dose as the GFR. It should be
noted, however, that there is no evidence for this practice.
BC Cancer Agency -Advises dialysis within 3 hours of giving dose.
GFR (ml/min)
>60
45-59
<45
Cladribine
Pro-drug - activated by intracellular
phosphorylation. The nucleotide
that is formed accumulates in the
cell and is incorporated into the
DNA. ~20% was recovered
unchanged in the urine.
SPC (Janssen Cilag 2008) – Acute renal insufficiency has developed in some
patients receiving high doses of cladribine. There is inadequate data on dosing
of patients with renal insufficiency.
SPC (Lipomed GmbH 2008) - Contraindicated in moderate to severe renal
impairment (CrCl</=50ml/min)
Janssen-Cilag – very limited information available. In a small study (n=9), it
was found that less than 30% of cladribine was excreted in the urine and less
than 10% was excreted as metabolite.
Clofarabine
Eliminated by a combination of
renal and non-renal excretion. After
24 hours 60% of the dose is
excreted unchanged in the urine.
Non-renal routes of elimination are
currently unknown.
SPC (Genzyme Therapeutics 2008) – No experience in this group of patients
(serum creatinine >2xUNL). Due to mechanism of excretion use with caution in
mild to moderate renal impairment and the drug is contraindicated in severe
renal impairment.
Bioenvision – as above
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Dose
100%
75%
consider
carboplatin
Consider carboplatin if GFR
<45ml/min
Conflicting information. Where GFR
is less than 45mls/min - clinical
decision.
Dialysis – give 50% dose. Dialysis
should be performed within 3 hours
after giving dose.
Lack of information available.
Clinical decision
Clinical decision likely to require
dose reduction. Contraindicated in
severe renal impairment.
Page 7 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
Crisantaspase
Plasma t½ is 7-13 hours.
SPC (Opi 2005) – no contraindications in renal impairment
UKALL2003 – no dose modifications listed for renal impairment
Clinical decision – unlikely to require
modification.
Cyclophosphamide
Pro-drug – converted by hepatic
microsomal enzymes to alkylating
metabolites (great inter-patient
variability in metabolism).
Excretion primarily renal. 30% is
excreted as unchanged drug. t½ is
4-10 hours in adults and 1-6.5 hours
in children.
SPC (Pharmacia 2007) – Not recommended in patients with a creatinine
>120mol/L.
Astra Medical - Patients with impaired renal function have been reported to
show an increase in metabolite concentration. Cyclophosphamide and its
metabolites can be eliminated by haemodialysis. Availability of mesna in the
urinary tract depends on renal function.
Lam et al 8– If CrCl > 10 ml/min, give 100% dose.
Renal Drug Handbook – 20-50 mls/min dose as in normal renal function, 1020mls/min 75-100% of normal dose,<10 50-100% of normal dose.
BC Cancer Agency –<10mls/min 75% dose otherwise 100%.
Dialysis
Baxter (Prev Asta Medical) – it is known that cyclophosphamide and its
alkylating metabolites can be eliminated by dialysis.9,10,11,12,13 In case of
complete anuria, neither cyclophosphamide, nor its metabolites should appear in
the urinary tract. The use of mesna concomitantly may therefore be unnecessary
in anuric patients. If there is any risk of cyclophosphamide or its metabolites
entering the urinary tract, mesna should probably be given to prevent urothelial
toxicity. It should be noted that complete anuria is extremely rare.
GFR (ml/min)
>20
10-20
<10
SPC (Hospira 2007) – Dose reduction does not appear to be necessary in
patients with impaired renal function. The human liver apparently detoxifies a
substantial fraction of the administered dose.
Faulding – When using high dose cytarabine (1-3g/m2) reduced doses should
be considered in patients with renal impairment7.
Pfizer – Dose reductions are not necessary when standard doses are used (100200mg/m2/24hrs). Reduced doses should be considered when using high dose
cytarabine in these patients.
BC Cancer Agency – for high dose therapy the following reductions should be
followed to reduce the risk of neurotoxi95city as this is directly associated with
renal function. See recommendations.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux, CAV/VVHD – full dose
for low dose regimes. Avoid in high dose regimes.
No dose reduction necessary
Cytarabine
Cytarabine is concentrated in the
liver. A major fraction of a dose is
inactivated by cytidine deaminase
in the liver and other body tissues.
After 24hrs, 80% dose has been
eliminated either as the inactive
metabolite or as unchanged
cytarabine, mostly in the urine, but
some in the bile.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Dose
100%
75%
50%
Clinical decision – consider whether
patient is being treated with high dose
treatment.
Dialysis
Renal Drug Handbook -dose at 50100% dose (CAPD, HD and
HDF/High flux) Do not perform
dialysis for 12 hours. Dose at 75100% dose (CAV/VVHD). If anuric,
mesna may not be required.
High Dose 1- 3g/m2:
GFR (ml/min)
Dose
>60
46-60
31-45
<30
Page 8 of 24
100%
60%
50%
CI
Drug
Dacarbazine
Pharmacokinetics
Available Information
Dacarbazine (DTIC) is assumed to
be inactive. Microsomal
metabolism in the liver produces
main metabolite; AIC. ~50% DTIC
is renally cleared. ½ of this is
unchanged DTIC & ~ ½ is AIC.
DTIC is renally tubularly secreted,
rather than glomerularly filtered.
SPC (Medac GmbH 2008) – If there is mild to moderate renal or hepatic
insufficiency alone, a dose reduction is not usually required. In patients with
combined renal and hepatic impairment elimination of dacarbazine is
prolonged. However, no validated recommendations on dose reductions can be
given currently.
Faulding – As the drug is excreted 50% unchanged in the urine by tubular
secretion, impairment of renal function is likely to necessitate a change in
dosage.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl
of 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, use 0.7 fraction of
dose.
Medac UK – Recommend dose adjustments as described by Kintzel et al.
Renal Drug Handbook – See recommendations.
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux. CAV/VVHD – 70%
dose
SPC (MSD 2006) – No information.
BC Cancer Agency – No adjustment required.
Renal Drug Handbook – Dose as in normal renal function, use with caution.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Dose as
in normal renal function.
SPC (BMS 2009) – Not studied in this group of patients but Since the renal
clearance of dasatinib and its metabolites is < 4%, a decrease in total body
clearance is not expected in patients with renal insufficiency.
Renal Drug Handbook – Dose as in normal renal function, use with caution.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD - Dose as
in normal renal function.
CrCl (ml/min)
Dose
45-60
30-45
<30
80%
75%
70%
SPC (Winthrop 2008) – A dose reduction is recommended in patients with
impaired renal function. See recommendations
Aventis – as SPC
BC Cancer Agency – Reduce dose by 50% if creatinine is greater than 265
mol/L
Dialysis
The Renal Handbook – CAPD, HD, CAV/VVHD - unlikely to be dialysed
Creatinine
/mol/L
Dose
<105
105-265
>265
100%
75%
50%
Dactinomycin
15% eliminated by hepatic
metabolism. ~30% of the dose was
recovered in the urine and faeces in
1week. The terminal plasma t½ ~
36hrs.
Dasatinib
Extensively metabolised in humans
by many enzymes.
Dasatinib is a substrate and
inhibitor of CYP3A4. Mainly
excreted in the faeces and 4% in the
urine.
Daunorubicin
Daunorubicin is rapidly taken up by
the tissues, especially by the
kidneys, liver, spleen and heart.
Subsequent release from of drug
and metabolites is slow (t½ ~
55hrs). Rapidly metabolised in the
liver & the major metabolite,
daunorubicinol is also active. It is
excreted slowly in the urine, mainly
as metabolites with 25% excreted
within 5 days. Biliary excretion
accounts for 40% elimination.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
Clinical decision – unlikely to require
a reduction.
Unlikely to require reduction
Page 9 of 24
Drug
Pharmacokinetics
Available Information
Cytochrome P-450 mediated
metabolism. In animal studies
distributed to all tissues and organs
except the brain. 6% and 75% of
the dose is excreted via the renal
and faecal route respectively within
7 days. Terminal t½ = 2.5 hours.
SPC (Sanofi Aventis 2008) – No information
Aventis – No dose adjustment necessary. 1 major and 3 minor metabolites have
been identified and these are excreted in the faeces.
Dialysis
Mencoboni et al, 2006 reported a case where the pharmacokinetics
of docetaxel, pre and post-dialysis administration in a haemodialised patient
were investigated. The results showed no apparent differences in the plasma
concentration-time curves of docetaxel administered before or after dialysis.
The authors concluded that docetaxel can be used in dialysis patients, with no
dosage reduction needed, with docetaxel not being removed from the blood
during dialysis14.
Renal Drug Handbook- CAPD, HD, HDF/High flux. CAV/VVHD - unlikely
dialysability – dose as in normal renal function.
No dose reduction necessary.
Doxorubicin
Mainly metabolised in the liver.
Rapidly cleared from plasma and
slowly excreted in the urine and
bile (50% of drug recoverable in the
bile or faeces in 7 days).
SPC (Hameln 2008) – Since doxorubicin and metabolites are excreted in the
urine only to a minor degree, there are no clear indications that the
pharmacokinetics or toxicity of doxorubicin are altered in patients with
impaired renal function.
Pharmacia – Yoshida et al15 have shown that the AUC of doxorubicin and
doxorubicinol (active metabolite) is significantly higher in patients with renal
failure. This study also suggests special attention should be paid to
haemodialysis patients receiving digoxin
BC Cancer agency – No adjustment required.
Renal Drug Handbook – No adjustment necessary
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux. CAV/VVHD – dose as
in normal renal function.
No dose reduction required. Clinical
decision in severe impairment.
Epirubicin
Mainly metabolised in the liver.
Slow elimination through the liver
is due to extensive tissue
distribution. 27-40% biliary
excretion. Urinary excretion
accounts for ~10% of dose in 48hrs.
SPC (Hameln 2008) – Moderate renal impairment does not appear to require a
dose reduction in view of the limited amount excreted by this route. Lower
starting doses should be considered in patients with severe renal impairment
(serum creatinine > 450 µmol/l).
BC Cancer Agency – lower starting doses recommended if serum creatinine
>442mol/L
Renal Drug Handbook – Dose as in normal renal function unless
GFR<10ml/min –then consider a dose reduction.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD – dose as
in normal renal function.
Dose reduce in severe impairment
only. Clinical decision.
Docetaxel
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
Dialysis
Dose as in normal renal function.
Page 10 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
Estramustine
Dephosphorylated in the intestines
then oxidised in the liver. 14-21%
excreted in the faeces and 22-36%
in the urine.
SPC (Pharmacia 2008) –Use with caution in renal impairment.
BC Cancer Agency – No adjustment required.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD – dose as
in normal renal function. Use with caution.
Probably no adjustment needed –
clinical decision.
Etoposide
Liver metabolised, yielding inactive
metabolites. ~45% of an
administered dose is excreted in the
urine, 29% being excreted
unchanged in 72 hrs. Up to 16%
recovered in the faeces.
SPC (medac GmbH 2007) – If GFR - >50ml/min ; 100% dose, 15-50mls/min;
75% dose, no specific information for GFR< 15ml/min however further dose
reduction should be considered. Subsequent etoposide dosing should be based
on patient tolerance and clinical effect.
BMS – Creatinine clearance is the strongest predictor of etoposide clearance.
US prescribing information suggest a 25% dose reduction for GFR between 15–
50 ml/min16. Subsequent dosing should be based on patient tolerance and
clinical effect. A further dose reduction should be considered with
GFR<15ml/min.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.85 fraction of dose, for CrCl
of 45ml/min, use 0.8 fraction of dose, for CrCl of 30ml/min, use 0.75 fraction of
dose.
Textbook of drug prescribing in renal failure and BC Cancer Agency –
GFR 10-50ml/min; 75% dose. Below 10 = 50% of dose.
Dialysis
Holthius et al17 reported comparable pharmacokinetics in patients receiving
haemodialysis for doses of etoposide up to 127mg/m2 in relation to patients with
normal renal function.
Sauer et al9 and Brindley et al18 found that etoposide is not removed by
dialysis.
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD – 50%
dose then base on clinical response.
CrCl (ml/min)
>50
15-50
<15
SPC ( Bayer May 2008) – If CrCl 30-70ml/min, then dose should be reduced
by up to 50% and close haematological monitoring should be used to monitor
toxicity. If CrCl <30 ml/min, fludarabine is contra-indicated.
Schering – as SPC
BC Cancer Agency – as SPC
Renal Drug Handbook – GFR 30-70mls/min use 50-75% of dose, 1030mls/min use 50-75% of dose but use with care. GFR<10mls/min use 50% of
dose and use with care.
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. – 50% dose, use with
care. CAV/VVHD – 50-75% dose, use with care.
CrCl (ml/min)
Dose
>70
30-70
<30
100%
50%
CI
Fludarabine
Rapidly dephosphorylated in
plasma to 2-F-ara-ATP, which is
necessary for cellular uptake. ~ 60%
of an administered dose is excreted
in the urine within 24hrs.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Dose
100%
75%
50%
Subsequent doses should be based on
clinical response.
Dialysis
Start at reduced dose and increase
according to clinical response.
Page 11 of 24
Drug
Pharmacokinetics
Available Information
Fluorouracil
Fluorouracil is distributed through
the body water. Activated in target
cells, catabolized in liver - most of
dose (80%) eliminated by liver
60-80% is excreted as respiratory
CO2 , 2-3% by biliary system
Following a single IV dose, ~15%
dose is excreted unchanged in the
urine.
SPC (Medac GmbH 2007) – Fluorouracil should be used with caution in
patients with reduced renal function.
Faulding –Bennett et al7 suggested that no dose adjustment is needed in renal
impairment.
BC Cancer Agency – No adjustments required
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux. CAV/VVHD – dose as
in normal renal function..
Consider dose reduction in severe
renal impairment only.
Gemcitabine
Rapid metabolism by cytidine
deaminase in the liver, kidney,
blood and other tissues. The active
intracellular metabolites have not
been detected in plasma or urine.
Urinary excretion of parent drug
and inactive metabolite (dFdU)
accounts for 99%.
Terminal t½ is ~1 hour – this
increases if the drug is administered
over a longer period.
SPC (Eli Lilly 2007) – Use with caution in patients with impaired renal
function.
Lilly – Since gemcitabine is extensively metabolised by various tissues, mild to
moderate renal insufficiency would not be expected to significantly affect its
clearance, although there is a possibility of accumulation of the inactive
metabolite, dFdU. Lilly investigated the Pharmacokinetics in 18 patients with
renal insufficiency and found that there was no significant difference between
patients on the basis of their GFR (GFR ranged from 30ml/min upwards).
Dialysis
Conventional intermittent haemodialysis should be performed before a weekly
dose and again some 48 hours later. Provided this is carried out the patient
should not face excess toxicity.
Renal Drug Handbook – Likely to be dialysed by CAPD, HD, CAV/VVHD,
HDF/High Flux.
No UK licence
Wyeth pharmaceuticals- The efficacy and safety profile of gemtuzumab
ozogamicin in patients with renal function impairment is relatively unknown.
One case report has shown success without excessive toxicity in a patient
receiving haemodialysis thrice weekly; however, more evidence is needed to
support its use in this patient population. There are no specific
recommendations for monitoring patients with renal impairment receiving
gemtuzumab ozogamicin therapy.
CrCl>30ml/min – standard dosing
CrCl<30ml/min – consider dose
reduction – clinical decision.
Gemtuzumab
The elimination of gemtuzumab
ozogamicin is hypothesised to be
principally via internalisation and
subsequent intracellular breakdown.
First, after binding to the CD33
antigen, gemtuzumab ozogamicin is
eliminated in the plasma by
internalisation into the cells.
Secondly, results from animal
studies suggest that the hepatic
excretory/metabolism route and
gastrointestinal secretion is
probably the major elimination
pathway, however, renal
elimination was seen to a smaller
extent. At this time the exact
elimination pathway in humans has
yet to be described.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
Dialysis
Likely to be dialysed but no
information on dosing.
Clinical decision
Page 12 of 24
Drug
Pharmacokinetics
Available Information
Hydroxycarbamide
(Hydroxyurea)
After oral administration,
hydroxyurea is readily absorbed
from the GI tract. 50% hepatically
metabolised. Peak plasma concn are
reached by 2hrs. 50% of a dose
recovered in urine within 12 hours,
mainly as intact drug. The rest is
excreted as carbon dioxide via the
lungs or via the urine as urea. t½ =
2-4 hours.
SPC (E.R Squibb 2006) - Use with caution in patients with marked renal
dysfunction.
BMS – Kintzel et al4 suggest for CrCl of 60ml/min; use 0.85 fraction of dose,
for CrCl of 45ml/min, use 0.8 fraction of dose, for CrCl of 30ml/min, use 0.75
fraction of dose.
Bennett et al19 suggest reducing the dose by half in patients with GFR
<10ml/min.
Renal Drug Handbook – GFR >60mls/min – give 85% of dose, 45-60mls/min,
80%dose, 30-45mls/min, 75% dose, 10-30ml/min, 50% dose, <10ml/min 20%
dose. Titrate according to response.
BC Cancer Agency- GFR >50ml/min- 100%; 10-50- 50% ;<10 - 20%
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux - 20% normal dose and
titrate to response. CAV/VVHD - 50% normal dose and titrate to response.
CrCl (ml/min)
Dose
>60
45-60
30-45
10-30
<10
85%
80%
75%
50%
20%
SPC (Pharmacia 2008) – in a number of Phase III clinical trials, treatment was
not given if Cr >177mol/L. For other anthracyclines, 50% dose reduce if Cr in
range 106-177mol/L. Contra-indicated in severe renal impairment.
Pharmacia – some studies have suggested that patients with Cr levels up to
350mol/L can be treated with oral idarubicin without dose modification.
BC cancer agency – Creatinine >200/mol/L give 50% dose
Dialysis
Renal Drug Handbook - CAPD, HD, HDF/High flux – Use 50% of dose with
caution. CAV/VVHD - Use 75% of dose with caution..
Creatinine
/mol/L
Dose
<100
100-175
>175
100%
50%
Clinical decision
Idarubicin
Oral idarubicin has rapid but erratic
absorption, about 30%
bioavailability. Extensive liver
metabolism to idarubicinol which
has equipotent activity and a much
longer t½ than idarubicin (50 vs
18hrs). Elimination is via the
hepatobiliary and renal system
mostly as idarubicinol. 17% (IV) /
8% (oral) is recovered in the faeces
over 5 days and 16% (IV) / 5%
(oral) is recovered in the urine over
4 days.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
.
Page 13 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
Ifosfamide
Pro-drug – converted by hepatic
microsomal enzymes to alkylating
metabolites. Excretion primarily
renal. ~80% dose excreted as
parent compound.
Serum t½ ranges between 4-8hrs.
SPC (Baxter 2006) – Risk factors to develop an encephalopathy are impaired
renal function (creatinine > 132µmol/L). Use is contra-indicated in renal
impairment.
Asta Medical – Dose reduction schedules established for cyclophosphamide
(which has similar metabolic pharmacokinetic parameters). Ifosfamide is
known to be more nephrotoxic than cyclophosphamide and has a CNS toxicity
profile. Availability of mesna in the urinary tract depends on renal function.
Renal Drug Handbook – GFR 20-50ml/min 75% dose; 10-20ml/min 75%
dose; <10ml/min 50% dose.
Euro-EWINGS protocol – Ifosfamide 9 g/m2 administered per course.
Protocol suggests to treat with 100% dose if GFR ≥ 60 ml/min. If GFR 40-59
ml/min, give 70% dose. If GFR <40 ml/min, use cyclophosphamide instead
(1500 mg/m2).
Dialysis
Renal Drug Handbook– CAPD, HD, HDF/High flux use 60% of normal dose.
Do not perform dialysis for at least 12 hours. CAV/VVHD use 80% of normal
dose.
BC Cancer Agency - dose as in <10ml/min at least 12 hrs before dialysis.
GFR (ml/min)
>60
40-59
<40
Imatinib
High oral bioavailability (98%).
Main circulating metabolite is Ndemethylated piperazine derivative.
Catalysed by cytochrome P450
CYP3A4
Mainly hepatic metabolism 68%
excreted in faeces and 13% in urine
in 7 days. t½ = 18 hours.
SPC (Novartis 2008) – Imatinib and its metabolites are not significantly
excreted via the kidney. Since renal clearance of imatinib is negligible, a
decrease in total body clearance is not expected in-patients with renal
insufficiency, However, in severe renal insufficiency caution is recommended.
BC Cancer Agency – No adjustment required.
Renal Drug Handbook – No adjustment to starting dose
Dialysis
Novartis – Case reported where imatinib has been used in end stage renal
disease while on haemodialysis. The pharmacokinetics of the parent drug and
metabolite were not altered. The author concluded the drug is safe to use at full
dose 14 for patient on haemodialysis, probably with renal failure
Renal Drug Handbook– CAPD, HD, HDF/High flux, CAV/VVHD. Dose as in
normal renal function.
SPC (Pfizer 2008) – not recommended in patients with impaired renal function
as studies in this population have not been done.
Aventis – as above
BC Cancer Agency - No dose adjustment required
Dialysis
Renal Drug Handbook – CAPD, HD, HDF/High flux - Reduce dose (50-80
mg/m2) and monitor closely. Increase as tolerated. CAV/VVHD - dose as in
normal renal function and monitor closely.
Stemmler et al20 - Patient treated with 80mg/m2 weekly without severe side
effects. Haemodialysis with irinotecan seems feasible. May be advisable to start
at a low dose e.g. 50mg/m2 and escalate slowly if tolerated.
No adjustment required.
Irinotecan
Metabolism is primarily hepatic,
where irinotecan is rapidly
converted to active metabolite SN38 by hepatic carboxylesterase
enzymes.
Excretion is predominantly biliary –
64% excreted in faeces. The mean
24hr urinary excretion of irinotecan
and SN-38 (its active metabolite)
was 19.9% and 0.25% respectively.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Dose
100%
70%
Clinical decision
Dialysis
Unlikely to require reduction.
No dose reduction needed, however
use with caution as no information in
this setting.
Page 14 of 24
Drug
Lenalidomide
Pharmacokinetics
Substantially excreted via kidneys
Available Information
Celgene- Dose reductions recommended for multiple myeloma and
myelodysplatic syndrome as adverse events have been shown to increase with
reduced GFR.
Dialysis
Renal Drug Handbook – CAPD – 15mg 2-3 times a week. HD, HDF/High
flux – 15mg 3 times a week post dialysis. CAV/VVHD - dose as in GFR 3050ml/min.
Recommendation
GFR
mls/min
>/=50
50<X>/
=30
<30
without
dialysis
<30
with
dialysis
Liposomal
Daunorubicin
Liposomal
Doxorubicin
Pharmacokinetic profile
significantly different to
daunorubicin, with a longer t½ and
a 200-400-fold reduction in volume
of distribution. Metabolism
appeared not to be significant at
lower doses. Clearance of the
liposomes may be mediated by the
reticuloendothelial cells with a
selective enhancement of uptake in
tumour cells. Anthracyclines are
excreted mostly through bile.
The plasma levels are 10-20-fold
higher than equivalent doxorubicin
doses. There is a preferential
retention of the drug in the
reticuloendothelial system, such as
liver, spleen and lungs. It appears
that the liposomal preparation
serves as a slow-release preparation
for free doxorubicin.
MM
MDS
25mg od
10mg dose
may be
increased
to 15mg od
after 2
cycles if
patient not
responding
15mg
q48hrs
10mg od
5mg od
15mg
3xweek
after
dialysis
5mg 3x
week
after
dialysis
5mg
q48hrs
SPC – no information.
Gilead Sciences –From American prescribing information. Where serum Cr
>265mol/L give 50% normal dose. Monitor toxicities in particular
cardiotoxicity.
Very little information.
If Cr >265mol/L, give 50% normal
dose.
SPC (Schering Plough 2008) – As doxorubicin is metabolised by the liver and
excreted in the bile, dose modifications should not be required for liposomal
doxorubicin. No information in patients with a GFR<30mls/min
No dose reduction needed.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Page 15 of 24
Drug
Lomustine
Melphalan
Pharmacokinetics
Available Information
Relatively rapid and complete oral
absorption, followed by first pass
metabolism. Part of lomustine
metabolism is mediated through
hepatic microsomal enzymes.
Metabolites predominantly excreted
by kidneys; 10% excreted as CO2
and <5% in faeces.
SPC (Medac GmbH 2007) – Kidney function should be assessed periodically.
Contraindicated in severe renal impairment.
BC Cancer Agency – if CrCl 10-50 ml/min, give 75% previous dose and if
CrCl < 10 ml/min, give 50% previous dose.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.75 fraction of dose, for CrCl
of 45ml/min, use 0.7 fraction of dose, for CrCl of 30ml/min, lomustine is not
recommended.
Renal Drug Handbook – GFR 45-60mls/min – 75% of dose, 30-45mls/min
give 70% of dose, <30mls/min – not recommended.
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD avoid.
SPC (GSK 2007) – Clearance, although variable, is decreased in renal
impairment.
For conventional IV doses (16-40mg/m2) & moderate – severe impairment,
reduce initial dose by 50% and subsequent dosage determined by
haematological suppression.
For high IV doses (100-240mg/m2) and GFR 30-50ml/min, reduce dose by 50%
Adequate hydration and forced diuresis are also necessary.
High dose melphalan is not recommended in patients with a more severe renal
impairment GFR<30mls/min.
GSK – as above. Some authors have suggested that it is not absolutely
necessary to withhold the drug in patients with severe renal impairment. The
initial dose should be reduced by 50% and adequate hydration and forced
diuresis should be used. Harousseau et al21 suggest using 60-120mg/m2 (rather
than 140mg/m2) if GFR 40-50ml/min
BC cancer agency – recommended dose adjustments available for nontransplant patients (see recommendations).
Tricot et al22 – Addressed safety of autotransplants in patients with a GFR
<40ml/min. The dose of 200mg/m2 was divided into two doses
(100mg/m2/day) and given on two consecutive days. This schedule did not
adversely affect the incidence of severe mucositis or overall survival. However,
it was associated with longer durations of fever and hospitalisation.
Dialysis
SPC (GSK 2007) -High dose melphalan with haematopoietic stem cell rescue
has been used successfully even in patients with dialysis dependant end stage
renal failure.
Renal Drug Handbook – CAPD, HD, HDF/High flux – dose as in
GFR<10ml/min. CAV/VVHD - dose as in GFR<10-20ml/min.
BC cancer Agency - Not removed from plasma to any significant degree by
hemodialysis, hemoperfusion, or peritoneal dialysis. Continuous arteriovenous
hemofiltration (CAVH): administer 75% of usual dose.
Incomplete and variable oral
absorption - 25-89% post oral dose;
AUC decreased by 39% when taken
with food.
Spontaneous degradation rather
than enzymatic metabolism.
Percentage of dose excreted in the
urine as active or toxic moiety
ranges from 11-93%. 20-50%
excreted in the faeces within 6
days. t½ ~ 1.5-2hrs.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Recommendation
CrCl (ml/min)
Dose
>60
45 - 60
30 - 45
<30
100%
75%
50%
not
recommended
GFR 30-50ml/min, give 50% dose.
For GFR <30ml/min, clinical
decision. Some sources suggest that
not necessary to withhold high dose
therapy – dose may be split on to 2
consecutive days.
Suggested Dosing for patients not
receiving BMT (IV or oral)
GFR >50mls/min, give 100% dose
GFR 10-50mls/min, give 75% dose
GFR<10mls/min, give 50% dose
Page 16 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
Mercaptopurine
Absorption of an oral dose is
incomplete, averaging ~50%. This
is largely due to first pass
metabolism in the liver (less when
given with food). There is
enormous inter-individual
variability in absorption, which can
result in a 5-fold variations in AUC.
It is extensively metabolised (by
intracellular activation). At
conventional doses clearance is
primarily hepatic. Renal clearance
may become important at high
doses.11 t½ = 1-3 hrs (PO) and 0.31 hr (IV).
SPC (GSK 2007) – Monitor renal function in the elderly. Consider reducing
dose in impaired renal function
BC Cancer Agency -With renal impairment, the use of the following dosing
intervals has been suggested: 24-36hrs for CrCl of 50-80ml/min, and 48hrs for
CrCl of 10-50ml/min23.
Clinical decision
Consider increasing dosing interval
as follows:
CrCl of 50-80ml/min – 24-36hrs
CrCl of 10-50ml/min – 48hrs
Methotrexate
The dose is well absorbed at doses
< 30mg/m2 – bioavailability is
decreased by food and milk.
Metabolism is via liver and
intracellular metabolism to
polyglutamated products.
The drug is excreted primarily by
the kidneys (>90%), although small
amounts via the bile. Clearance is
higher in children than in adults. t½
~ 8 hrs.
SPC (Hospira 2009) – Significantly impaired renal function is a contraindication.
Wyeth – Renal clearance correlates with CrCl. Methotrexate t½ is inversely
related to CrCl.
Kintzel et al4 - suggest for CrCl of 60ml/min; use 0.65 fraction of dose, for
CrCl of 45ml/min, use 0.5 fraction of dose, for CrCl of 30ml/min, methotrexate
is not recommended.
BC Cancer Agency – suggested dose modification GFR; 61-80 give 75% dose;
51-60 =70%, 10-50 30-50%; <10 =CI
Renal Drug Handbook - GFR >50ml/min use 100% dose; GFR 10-50ml/min
use 50% dose; GFR<10ml/min – avoid.
Dialysis
Bennett et al, 1999 - Give 50% dose7.
Renal Drug Handbook - Contraindicated in CAPD. Dialysed in HD and
HDF/High flux. Use 50% of the normal dose at least 12hrs before next dialysis.
Use with caution. CAV/VVHD – use 50% of normal dose.
CrCl (ml/min)
Dose
>80
60
45
<30
100%
65%
50%
CI
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Page 17 of 24
Drug
Pharmacokinetics
Available Information
Pro drug activated in vivo.
Metabolism is predominantly in the
liver. The rate of clearance is
inversely proportional to the
maximal serum concn, due to
saturation of the degradative
pathways. ~10% is excreted
unchanged in the urine. Since
metabolic pathways are saturated at
low doses, the % dose excreted in
the urine increases with increasing
dose.
SPC (Kyowa Hakko 2007) – No information on dose adjustment. Severe renal
toxicity has occasionally been reported after treatment and renal function should
be monitored before each course.
Fischer D et al23 suggest the following:
For GFR 10-60ml/min, use 75% dose, for GFR <10ml/min, use 50% dose.
Renal Drug Handbook – GFR >10ml/min use 100% dose GFR <10ml/min use
75% dose
Dialysis
Renal Drug Handbook – HD, CAPD and HDF/High flux dose as in GFR
<10mls/min (75% dose). CAV/VVHD dose as in normal renal function.
Mitotane
Metabolised by both liver and
kidneys. 60% excreted unchanged
in faeces. Small proportion in bile
as metabolites. 10-25% excreted in
the urine as metabolites.
SPC (HRA pharma labs 2008) – No experience in this group therefore use in
caution in mild to moderate renal impairment and contraindicated in severe
renal impairment.
BC Cancer agency – Dose adjustment required but no details found.
Clinical decision – dose reductions
required.
Mitoxantrone
Extensive metabolism in the liver.
Excretion is predominantly bile and
faeces. 5-10% of dose is excreted
in the urine within 5 days.
SPC (Wyeth 2008) – No information
Wyeth – Dose reductions appear to be unnecessary in patients with reduced
renal function. The principal dose-limiting side effect is myelosuppression,
which should be monitored. Mitoxantrone does not appear to be eliminated by
haemodialysis and dose adjustments are not needed in such patients.
BC Cancer Agency – No dose reduction required
No dose reductions necessary.
Mitomycin C
Recommendation
GFR (ml/min)
Dose
>10
100%
<10
75%
Consider a dose reduction for high
doses of mitomycin when GFR 10-60
ml/min.
Dialysis – Haemodialysis and CAPD
dose as in GFR <10mls/min (75%
dose)
Dialysis
Extensively tissue bound therefore unlikely to be eliminated by haemodialysis
or peritoneal dialysis. Dose adjustments may not be needed in patients
undergoing this procedure13
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD – not
dialysed, dose as in normal renal function
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Page 18 of 24
Drug
Oxaliplatin
Paclitaxel
Pentostatin
Pemetrexed
Pharmacokinetics
Available Information
Recommendation
In vitro, there is no evidence of
cytochrome P450 metabolism.
Extensive nonenzymatic
biotransformation occurs. Platinum
is excreted mainly by renal
excretion and tissue distribution,
while platinum metabolites are
mainly by renal excretion. By day
5, ~54% of the total dose was
recovered in the urine and <3% in
the faeces.
SPC (Sanofi-Aventis 2007) – Oxaliplatin has not been studied in patients with
severe renal impairment (<30ml/min). In patients with moderate renal
impairment, treatment may be initiated at the normally recommended dose.
Consider risk/benefit ratio. There is no need to dose reduce in patients with
mild renal dysfunction.
Sanofi – Massari C et al24 looked at patients with normal and impaired (2757ml/min) renal function. Data showed the same plasma levels between the 2
groups, and the clearance of both total and free platinum as well as AUC
correlated with the CrCl. Toxicities were similar in the 2 groups.
Takimoto CH et al25 – Data found to support the recommendation that dose
reductions of single-agent oxaliplatin are not necessary in patients with a CrCl
greater than 20ml/min (dose based on 130mg/m2 every three weeks).
BC Cancer Agency- GFR >30ml/min 100%, < 30ml/min – No information.
Dialysis
Sanofi – It is not anticipated that dialysis treatment during oxaliplatin therapy
would cause any problems.
Moderate renal impairment – treat at
normal dose, and monitor renal
function. Dose adjust according to
toxicity.
Hepatic metabolism and biliary
clearance is the principal
mechanism for disposition. Mean
values for cumulative urinary
recovery of unchanged drug ranged
from 1.3 to 12.6% of the dose,
indicating extensive non-renal
clearance.
SPC (Abraxis Bioscience 2009) – No recommendations
BMS – within 24-48 hrs following administration, <10% of the dose appears in
the urine. In dialysis patients, full dose has been given (on non-dialysis days)
with a typical toxicity profile.
Dialysis
26
- Paclitaxel chemotherapy is efficacious and feasible for patients undergoing
haemodialysis (NB study was carried out in ovarian cancer at 150mg/m2).
Bekele et al 2001- reports a case of a patient that receives paclitaxel whilst on
haemodialysis. The authors recommended dose reduction (135mg/m2) in
dialysis patients 27.
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function
BC Cancer Agency – No adjustment necessary
SPC (Hospira 2009) – Results from a published study in 13 patients with
impaired renal function suggested the following dosage adjustment. Dosage was
adjusted to 75% at a CrCl of 40-59 ml/min (3 mg/m2) and to 50% at a CrCl of
35-39 ml/min (2 mg/m2). There are insufficient data to recommend a starting or
a subsequent dose for patients with creatinine clearance < 35 ml/min. Given
limited data, if CrCl <60 ml/min, pentostatin is contra-indicated.
No dose reductions necessary.
SPC (Eli Lilly 2009) – Drug can be safely given if GFR>45mls/min, lower than
this adjustments cannot be recommended.
Lilly – Case report of a patient receiving grade 3-4 toxicity after administration
with a GFR 19mls/min.
BC Cancer Agency - GFR<45 delay treatment
GFR>45mls/min 100% dose
Otherwise clinical decision
May be hazardous in severe renal
impairment.
Only a small amount is
metabolised. It is primarily
excreted unchanged by the kidneys
- 30 – 90% excreted by kidneys
within 24 hours.
Not metabolised to an appreciable
extent. Mainly excreted (70-90%)
unchanged in the urine.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
CrCl <20m/min –dose reduce
Dialysis
It is not anticipated that dialysis
treatment during therapy would cause
any problems.
Dialysis – clinical decision
CrCl
(ml/min)
Dose
>59
40-59
35-39
<35
100%
75%
50%
not recommended
Page 19 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
After oral absorption, the drug
appears to be rapidly and
completely absorbed. Procarbazine
is metabolised by microsomal
enzymes in the liver to an active
alkylating agent. After 24hrs up to
70% of a dose is recovered in the
urine.
Not metabolised. 40-50% is
excreted unchanged in the urine.
15% of dose is excreted in the
faeces over a 10-day period. Active
tubular secretion may contribute to
the renal excretion11
Mean serum t1/2 increases with dose
and repeated dosing - 76.3 hours
after 1st infusion and 205.8 hours
after 4th infusion.
Detectable in body for 3-6 months.
SPC (Cambridge 2006) – Caution advisable in patients with renal dysfunction.
Tricot et al 199622 - With serum creatinine >177mol/L, doses should be
substantially reduced.
Lack of available information.
If serum creatinine >177mol/L, give
50% dose.
Temozolomide
Temozolomide is rapidly and
completely absorbed with 100%
bioavailabiltiy. Tissue distribution
is extensive. t½ is ~1.8hrs. The
major route of elimination is renal.
~5-10% is excreted unchanged and
the remainder as metabolites.
Thalidomide
Exact metabolism is unknown.
Possible spontaneous hydrolysis in
the plasma.0.7% excreted
unchanged in the urine. There is
minimal hepatic metabolism and
urinary excretion of thalidomide.
SPC (Schering-Plough 2009) – No data in renal dysfunction. Analysis of
population pharmacokinetic data revealed that plasma temozolomide clearance
was independent of age and renal function. It is unlikely that dose reductions
are required in patients with renal dysfunction.
BC Cancer agency – No dose reduction required
Renal Drug Handbook – Dose as in normal renal function.
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function..
SPC (Celgene 2008) – Thalidomide Pharmion has not formally been studied in
patients with impaired renal function. No specific dose recommendations for
these patient populations are available. Patients with severe organ impairment
should be carefully monitored for adverse reactions
Pharmion – Doses in patients with renal impairment should be titrated with
observed tolerance and toxicity and the highest tolerated dose should be
selected. Since renal insufficiency is common among multiple myeloma
patients, the recommended adult dosage has been established in populations of
patients including those with renal impairment.
Renal Drug Handbook – Dose as in normal renal function
BC Cancer Agency – No dose reduction required
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function.
Procarbazine
Raltitrexed
Rituximab
For severe renal impairment – not
recommended.
SPC (Astra Zeneca 2002) – See recommendations
Renal Drug Handbook – As guidelines.
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD.
Unlikely to be dialysed – avoid use.
SPC (Roche 2008) – No information
BC Cancer Agency – No dose reduction required.
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
CrCl ml/min
Dose
Interval
>65
100%
3 wkly
55-65
75%
4 wkly
25-54
50%
4 wkly
<25
0%
Probably no dose reduction
necessary.
Probably no dose reduction
necessary.
No dose reduction necessary.
Page 20 of 24
Drug
Pharmacokinetics
Available Information
Recommendation
Thioguanine
Variable and incomplete oral
absorption with 14-46%
bioavailability. Extensive
metabolism in the liver and other
tissues to several active and
inactive metabolites. 24-46% of the
dose is excreted in the urine
within 24 hours.
SPC (GSK 2008) – Consideration should be given to reducing the dosage in
patients with impaired hepatic or renal function.
BC cancer agency – Dose adjustments recommended but no values.
Consider dose reduction, but no
formal recommendations.
Thiotepa
Metabolised in liver to triethylene
phosphoramide (TEPA) Only traces
of unchanged thiotepa and (TEPA)
are excreted in the urine, together
with a large proportion of
metabolites (60% within 72 hours).
SPC (Cyanamid 2004) – No information.
Wyeth – No information.
BC Cancer agency – Adjustment required but no information.
Lack of information available.
Consider dose reduction, but no
formal recommendations.
Tipifarnib
Unknown
Ortho Biotech –No clinical studies have been conducted in this group of
patients. A population pharmacokinetic analysis indicated that there was no
relationship between tipifarnib clearance and creatinine clearance.
Clinical decision – unlikely to require
a dose reduction.
Topotecan
Undergoes reversible, pHdependent hydrolysis of the active
lactone moiety to the inactive
hydroxyacid (carboxylate) form. A
relatively small amount of
topotecan is metabolised by hepatic
microsomal enzymes to an active
metabolite, N-demethyltopotecan.
The clinical significance of this
metabolite is not known.
Excretion via biliary and renal
route. 20-60% is excreted in the
urine as topotecan or the open ring
form.
SPC (GSK 2009) – There is no experience of the use of topotecan in patients
with CrCl < 20 ml/min and topotecan is contra-indicated in this group of
patients. Plasma clearance in patients with CrCl 41-60ml/min is decreased to
~67%. In moderate renal impairment, plasma clearance was reduced to ~34%.
Merck – Dose-limiting toxicities, mainly neutropenia and thrombocytopenia
are seen in patients with impaired renal function. In patients with moderate
renal impairment, a starting dose of 0.75mg/m2 is recommended. Further
reductions are recommended in heavily pre-treated patients.
Kintzel et al4 suggest for CrCl of 60ml/min; use 0.8 fraction of dose, for CrCl
of 45ml/min, use 0.75 fraction of dose, for CrCl of 30ml/min, use 0.7 fraction of
dose.
BC Cancer Agency-GFR 40-60ml/min =100% dose, 20-39= 50%, < 20 =not
recommended.
Dialysis
Topotecan is effectively cleared by HD. Plasma clearance may be increased
fourfold whilst on HD28.
Renal Drug Handbook – CAV/VVHD – 0.5-0.75mg/m2/day and monitor
closely.
CrCl (ml/min)
Dose
>40
20-39
<20
100%
50%
CI
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Page 21 of 24
Drug
Pharmacokinetics
Probably no dose reduction
necessary.
Maximum absorption levels
reached within 1-2hrs. Conversion
of tegafur to 5-FU occurs via
microsomal (CYP2A6) and
cytosolic enzymes. The
metabolism of 5-FU follows the
natural pathways for uracil. Less
than 20% of tegafur is excreted
intact into the urine. The 3
hydroxy-metabolites are excreted in
the urine.
Vinblastine is extensively
metabolised, primarily in the liver
to desacetylvinblastine, which is
more active than the parent
compound. 33% of the drug is
slowly excreted in the urine and
21% in the faeces within 72 hours.
SPC (Merck Serono 2008) – Use with caution in patients with renal
impairment. There is no experience with the UFT/calcium folinate combination
in patients with renal impairment. Physicians should exercise caution.
BMS – The effect of renal impairment on the excretion of UFT has not been
assessed. Although the primary route of elimination of UFT is not renal,
caution should be exercised in patients with impaired renal function. Monitor
closely.
Lack of information available.
Probably no dose reduction necessary
Monitor for toxicity.
SPC (Hospira 2004) – No information.
Faulding – No dose reduction necessary.
Renal Drug Handbook – No dose reduction
BC Cancer Agency – No dose adjustments necessary.
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function.
No dose reduction necessary
Metabolised by cytochrome P450
(in the CYP 3A subfamily).
Elimination is primarily biliary excreted into bile and faeces (67%
within 72 hours, 40-50% as
metabolites). 10% excreted in urine
in 24hrs.
SPC (Hospira 2004) – no information.
Lilly – no dose reduction necessary.
Renal Drug Handbook – no dose reduction required.
Dialysis
Mayne - Not dialysable in vitro but these results cannot be automatically
transferred to an in vivo situation
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function.
No dose reduction necessary
Distributes to normal cells, tumour
cells and serum where HER2
antigens are found. t1/2 = 28.5 days.
Remains in body for 24 weeks
Doesn’t require hepatic or renal
metabolism for elimination.
Treosulphan
Treosulfan is a pro-drug of a
bifunctional alkylating agent. High
and relatively constant
bioavailability. The mean urinary
excretion of the parent compound is
~15% over 24hrs.
UFT
(Tegafur-uracil)
Vincristine
Recommendation
SPC (Roche 2009) – Dedicated studies in patients with renal or hepatic
impairment have not been carried out. However, in a population
pharmacokinetic analysis, renal impairment was not shown to affect
trastuzumab disposition.
BC Cancer Agency – No dose adjustments necessary.
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function.
SPC (Medac GmbH 208) – No information.
Medac – No information for GFR >30mls/min, If GFR<30ml/min reduce dose
by approximately 40%.
Trastuzumab
Vinblastine
Available Information
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Lack of information available.
Clinical decision.
Page 22 of 24
Drug
Pharmacokinetics
Vindesine
Metabolised by cytochrome P450
(in the CYP 3A subfamily).
Elimination is primarily biliary.
(13% excreted in urine in 24hrs).
Vinorelbine
Widely distributed in the body,
mostly in spleen, liver, kidneys,
lungs, thymus; moderately in heart,
muscles; minimally in fat, brain,
bone marrow. High levels found in
both normal and malignant lung
tissues, with slow diffusion out of
tumour tissue. Metabolism appears
to be hepatic. t½ is greater than
40hrs. Excretion is mainly by the
biliary route (18.5% appears in the
urine)
Available Information
SPC (Genus 2004) – no information.
Lilly – no dose reduction necessary.
BC Cancer Agency – No dose adjustments necessary
Dialysis
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function.
SPC (Medac GmbH 2007) – There is no pharmacokinetic rationale for
reducing vinorelbine dose in patients with impaired kidney function.
Pierre-Fabre – Clearance is mainly hepatic.
Renal Drug Handbook – No dose reduction.
BC Cancer Agency – No dose adjustments necessary.
Dialysis
BC Cancer Agency - Reduction from 25 mg/m² to 12.5 mg/m² IV for one dose
on day 1 weekly (given after hemodialysis) was reported in one patient.
Renal Drug Handbook – HD, CAPD, HDF/High flux and CAV/VVHD –
Dose as in normal renal function and monitor closely.
Recommendation
No dose reduction necessary
No dose reduction necessary
References:
1 Inauen et al. Oncology,2007;72:209-210
2 Mansi J, da Costa F, Viner C. J Clin Oncol 1992;10:1569-1573
3 Ullery LL et al. Bone Marrow Transplantation. 2000:25, 201-203.
4 Kintzel PE, Dorr RT. Cancer Treat Rev 1995;21:33-64
5 The Renal Drug Handbook, Ashley C & Currie A Radcliffe Medical Press, Oxford 3 rd ed 2009
6 Boesler et al. Nephrology Dialysis Transplantation. 2005:20, 1187-1191
7 Bennett WM et al. Dosing Guidelines for Adults. 4 th ed. American College of Physicians, 1999.
8 Lam MSH et al. JOPP, 2003:9;45-85
9 Sauer H et al Cancer Treatment Rev 1990:17(2&3): 293-200
10 Bending, MR, Finch, RE. BMJ, 1978;1: 820-821
11 Milstead,RAV,Jarman,M, BMJ,1978;1: 1145-1146
12 Wang LH et al Clin. Pharmacol. Ther, 1981;29: 365-372
13 Boros,L et al Cancer Chemother Pharmacol 1992; 31 (1): 57-60
14 Mencoboni et al. Chemotherapy 2006:52,147-150
15 Yoshida H et al. Cancer Chemother Pharmacol, 1994,33;450-454
16 Vepesid prescribing information; Physician’s Desk Reference 1999
17 Holthius JJM et al Cancer Treat Rep 1985;69:1279-1282
18 Brindley Cj et al Cancer Chemother Pharmacol 1985;15(1): 66-71
19 Bennett WM et al. Am J Kidney Dis 1983;3:155-193
20 Stemmler J et al Onkologie 2002;25(1):60-63
21 Harousseau JL et al Blood 1992;79:2827-2833
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Page 23 of 24
22
23
24
25
26
27
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Tricot G et al Clin Cancer Res 1996 Jun;2(6):947-52
The Cancer Chemotherapy Handbook, Fischer D, Tish Knobf M, Durivage H. 4 th Ed ((Mosby)
Massari C et al. Cancer Chemother Pharmacol, 2000,45;157-164
Takimoto CH et al Journal of Clinical Oncology Jul 15 2003: 2664-2672
Tomita et al Anti-Cancer Drugs 2001;12:485-487
Bekele et al. Am J clin Oncol. 2001. 24, 382-384
Herrington et al Cancer Chemother Pharmacol 2001;47(1):89-93
Compiled by:
Checked by:
Revised by:
Checked by:
Revised by:
Checked by:
Review Date:
Susanna Daniels, March 2001
Max Summerhayes, April 2001
Sumantha Gabriel Sept 2003
Susanna Daniels Nov 2003
Pinkie Chambers Sept 2008
Emma Riches Jan 2009
September 2011
UCLH - Dosage Adjustment for Cytotoxics in Renal Impairment (Version 3 - updated January2009)
Page 24 of 24